The syndemics of addiction, HIV and TB are concentrated in criminal justice settings (CJS). HIV and TB contribute most to mortality among the ~50-60 million people who transition through prisons annually. Malaysia has the highest HIV prevalence among people who inject drugs (PWIDs) in Asia where criminalization of drugs is harsh, resulting in the highest HIV prevalence among prisoners and the second highest incarceration rate in Asia. While mortality decreased 39% in Asia, it has increased in Malaysia where treatment of HIV and TB are inadequately treated among PWIDs, especially in prisoners. Over the past 10 years, researchers at Yale University and the University of Malaya have continuously collaborated on research involving key populations, including PWIDs, prisoners, MSM and both female and transgender sex workers. Our research has multidisciplinary at the interface of addiction and infectious diseases like HIV, TB, HCV and sexually transmitted infections. Our research has been supported through funding for a number of pre- and post-doctoral students and junior faculty members through our Fogarty-sponsored Global Health Equity Scholars program, Doris Duke Charitable Global Health Training, Fulbright scholarships and through NIDA-sponsored research grants. Central to our research activities have been a number of findings from our prison-based studies that inform the current R01 submission, including: Accomplishments from these aims that support the next generation of research questions include: 1) extraordinary mortality among HIV+ prisoners, primarily form TB; 2) high prevalence of latent TB infection (LTBI) among HIV+ and HIV- prisoners and prison personnel alike; 3) the emerging role of prisoners as high risk environments contributing to onward TB transmission among prisoners transitioning to the community; 4) effectiveness of opioid agonist therapies (OAT) like methadone and buprenorphine in promoting retention in care and improved HIV and TB outcomes in community settings, including among released prisoners; 5) despite these promising findings from OAT, negative attitudes by prisoners and correctional staff toward their use undermine their potential benefits; and 6) preliminary studies challenging existing recommendations for TB screening, diagnostics and prevention strategies in prisons that are central to the two related and sequential specific aims in this proposal: 1) To conduct empiric studies of TB, including: a) TB diagnostics (symptoms, CXR, TST, AFB smear, Gene Xpert, and sputum culture) to optimize TB screening; b) a RCT of TB prevention strategies among HIV+ and HIV- prisoners comparing a 12-week short-course of once-weekly isoniazid/rifapentine vs a standard 40-week course of daily isoniazid in a population with high HCV prevalence and potential for hepatotoxicity; and c) a RCT of HIV= and HIV- prisoners with TB who have insufficient time to complete treatment within prison and comparing treatment completion rates for those who refuse OAT with those who accept it, but who are randomized to methadone or buprenorphine therapy to facilitate continuity of care post-release; and 2) To use data from aim 1 combined with publically available TB data to conduct agent-based modeling for comparative and cost- effectiveness analyses of TB screening, prevention and treatment strategies among prisoners with and without HIV, incorporating the contribution of latent TB infection and prevalent TB disease on community transmission post-release.